In subjects affected by cardiovascular pathologies such as aortic stenosis, chronic arterial hypertension, valvular dysfunction, myocardial infarct, myocarditis, idiopathic cardiomyopathy, is subjected to increased workload. The presence of a pathological insult induces the heart to undergo hypertrophy, a tissue remodelling program aimed at maintaining cardiac function. Although cardiac hypertrophy is, thus, initially compensatory and beneficial, under condition of chronic pathological stimuli, additional events might occur that either reduce the efficacy of the hypertrophy response or activate additional pathways causing cardiac dilation and progressively leading to heart dysfunction and failure.
Melusin functional properties can provide a highly innovative and robust approach to counteract the evolution toward heart dysfunction and failure.
Melusin, in fact, is selectively expressed in skeletal muscle fibers and cardiomyocytes (Brancaccio et al., 1999), and it is required to activate a compensatory cardiac hypertrophy program in response to stress conditions such as chronic pressure overload of the left ventricle (Brancaccio et al., 2003). Such a function requires the activation of AKT/GSK3beta and of ERK (Brancaccio et al., 2003) (De Acetis et al., 2005), two well known signaling pathways in cardiac hypertrophy.
Forced expression of melusin in heart of transgenic mice efficiently protects from left ventricle dilation and failure when heart is subjected to prolonged pressure overload (De Acetis et al., 2005).
In human patients affected by dilated cardiomyopathy in response to aortic stenosis reduction melusin expression parallels the functional cardiac impairment as measured by ejection fraction values (Brokat et al 2007).
Current leading medications for the treatment of Heart Failure (CHF) include drugs targeted to hemodynamic overload (diuretic and nitrates), to inhibit the activity of both renin-angiotensin (ACE-inhibitors and sartans) and sympathetic nervous system (beta-blockers). Although development of these drugs has led to better treatment, 50% of the patients with the most advanced stage of heart failure die within a year, the heart transplant still being the only cure. Indeed, most, if not all, available drugs are mainly aimed to reduce cardiac hemodynamic overload by reducing blood pressure and undesirable consequences of heart failure on different peripheral organs.
Thus, therapeutical approaches aimed to correct the major defects in cardiac muscle at the basis of heart failure represent a major current medical need as they should provide a much more effective outcome compared to inotropic therapy or mechanical devices assisting heart function.